The overall objective of this study is to achieve a better correlation between the hepatic ultrastructure and the functional aspect of bile secretion and cholestasis using animal experimental models. Specific aims are: 1) to study the functional significance of the bile canalicular ultrastructure with respect to a) changes associated with cholestasis and choleresis induced by bile acids, chlorpromazine and other agents, b) histochemical localization of Na ion K ion-ATPase and c) attached microfilaments; 2) to study the possible contribution of paracellular fluid transport to bile secretion and stasis with reference to a) histochemical localization of Na ion, K ion ATPase and its relationship with the bile acid-independent fraction of bile flow, and b) permeability of the junctional complexes; 3) to study morphological localization of bile acid in the hepatic tissue, its pathophysiological significance, 4) to identify bile secretory organelles and characterize their changes in cholestasis, and 5) to study the cholestatic and hepatotoxic effects of bile acids, especially 3-beta hydroxy cholenoic and ursodexycholicacids. In order to achieve these goals, cholestasis and choleresis will be induced in rats and rabbits by the administration of cholestatic and/or choleretic bile acids either singly or in combination. Chlorpromazine, ethynyl estradiol and scillaren will also be used. Structural and functional changes induced in the liver by these treatments will be examined by combination of some or all of the following methods: light microscopy, scanning and transmission electron microscopy, enzymatic and other types of histochemistry, autoradiography, ultrastructural tracers, biochemical determination of serum enzymes and other functional parameters.